Common Protocol Template Asthma Library V2.0

Common Protocol Template Asthma Library v2.0

Common Protocol Template Asthma Library v2.0

Section in Common Protocol Template (CPT) / Library Content

1.Protocol Synopsis Objectives and Endpoints

/ Protocol Synopsis Objectives and Endpoints
4.Objectives and Endpoints / Objectives and Endpoints
5.Study Design / Instructional text including Definitions of Common Assessments
10.3 Statistical Analyses / Instructional text
11.References / References applicable to the Asthma library
Pulmonary Function Test Manual (not included with this template) / Instructional text on suggested content for the Pulmonary Function Test Manual (not included with this template)

Synopsis Objectives and Endpoints
and
4. Objectives and Endpoints (main body)

Endpoints:

The choice of endpoints depends on the characteristics of the study treatment and potential indication. Study treatments for the immediate relief of symptoms may have a different array of endpoints from those designed for long-term control.

Forced Expiratory Volume in 1 second (FEV1) is the volume (L or mL) of air that is exhaled in the first second of a forced spirometry test.
Forced Vital Capacity (FVC) is the volume (L or mL) of air expired over the course of a forced, maximal exhalation after a full inhalation. It is equal to the sum of inspiratory reserve volume, tidal volume, and expiratory reserve volume.
FEV1 correlates more closely with reversibility of airflow obstruction, whereas FVC may increase merely due to longer expiration. The American Thoracic Society (ATS) and European Respiratory Society (ERS) defines a significant response as an increase in either FEV1 or FVC of more than 12% of the baseline value and > 200 mL, (Reddel, 2009).

Objectives / Endpoints
Primary
A single objective can support primary and secondary functional endpoints (FEV1, FVC, FEV1/FVC ratio, and control [reduction] of asthma symptoms). Severity of asthma defines the participant population per ATS guidelines (Reddel, 2009); often the participant population has ‘moderate’ or ‘severe’ asthma.

To evaluate the efficacy of [x mg of Study Treatment] administered [frequency] to subjects with [severity of asthma] asthma

To evaluate the efficacy of [x mg of Study Treatment]administered [frequency] compared with [comparator] in participants with[severity of asthma] asthma

/ Spirometry FEV1
If utilizing spirometry FEV1, FVC, and/or FEV1/FVC Ratio or % endpoints, create a Pulmonary Function Test (PFT) Manual as a separate document to provide details on PFT assessments.
Spirometry FEV1 Endpoints:
Common measures of efficacy in asthma studies include FEV1 and FVC. The FEV1 is most reproducible of all spirometry measuresbecause most individuals can generate maximal effort for 1second. Thus, it is highly regarded as a reliable and consistent primary efficacy endpoint. The remaining spirometric measures can be key secondary or secondary endpoints.

The absolute change in the percentage of predicted FEV1 from baseline to [Week X]

The increase [magnitude of change] in FEV1 from baseline to [Week X]

Section 10 Statistical Considerations of the protocol should provide details on the selected primary endpoint, the variables that will be collected, the timepoints, and the statistical methods that will be used to analyze the primary (or key secondary) endpoints.
Secondary

To evaluate the efficacy of [x mg of Study Treatment] administered [frequency] to subjects with [severity of asthma] asthma

To evaluate the efficacy of [x mg of Study Treatment]administered [frequency] compared with [comparator] in participants with [severity of asthma] asthma

/ Forced Vital Capacity(FVC)

The absolute change in the percentage of predicted FVC from baseline to [Week X]

Section 10 of the protocol should provide details on the selected secondary endpoint, the variables that will be collected, the timepoints, and the statistical methods that will be used to analyze the key secondary endpoints.
FEV1/FVC Ratio or %

The change from baseline in FEV1/FVC (or change in the percentage from baseline) to [Week X]

Asthma Symptoms
Asthma Symptom Endpoints:
The most common symptoms of asthma include shortness of breath, cough, wheezing, chest tightness, and nocturnal awakenings. Validated questionnaires exist to assess the symptoms of asthma.
Refer to CDISC Therapeutic Area User Guide Appendix E: Questionnaires for a list of commonly used questionnaires to assess symptoms (CDISC, 2013). These questionnaires are validated and have copyrights; the protocol author is advised to review the copyright requirements prior to selection of the tool to assess asthma symptoms. The Asthma Control Questionnaire (ACQ) and the Asthma Control Test (ACT) are the most frequently used instruments.
The reduction of symptoms, as demonstrated by the [questionnaire]
Provide a clinically meaningful composite score for the selected instrument.
Section 10 of the protocol should provide details on the selected composite score (detailed rationale) for the selected instrument and the analytical methods that will be applied. Section 10 should include cross references to the statistical analysis plan (SAP) as needed.
Clinical Asthma Exacerbations (CAEs)
Asthma Exacerbation Endpoints: These are transient worsening of asthma and define events which change the patient’s health status. These are characterized by decreases in expiratory flow, increases in symptoms, and increased use of bronchodilators. A reduction in CAEs is an anticipated outcome in all asthma clinical trials.

The incidence of severe CAEs compared to control at [Week X]
The incidence of moderate CAEs compared to control at [Week X]

Examples of CAEs include the following:

Hospitalization, emergency room (ER), or Urgent Care (UC) treatment with systemic steroids
Initiation or increased dose (from a stable maintenance dose) of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days to prevent a serious outcome
Asthma-specific ICU admissions/intubations
Asthma-related deaths

If CAE endpoints are selected, then include the following concepts in Section 10.3 of the protocol

Identify steroid equivalents that will be used to document an increased dose (when switching from one steroid to another)
Exacerbations must be defined as moderate or severe. The following definitions for severe and moderate CAEsare based on ATS/ERS Guidelines, (Reddel, 2009).

Severe CAE: Event that requires urgent action on the part of the participant and physician to prevent a serious outcome, such as hospitalization or death from asthma.
Provide details on how severe exacerbations will be analyzed.
Moderate CAE:Event that istroublesome to the participant and prompts a need for a change in treatment, but is not severe.
Provide details on how moderate exacerbations will be analyzed.
Moderate and severe events are clinically identified asbeing outside the participant’s usual range of day-to-day asthma variation. A ‘mild’ exacerbation is just outside the normal range of variation for the individual and cannot be distinguished from transient loss of asthma control; hence no definition is provided.
Rescue Medication

The reduction in number of rescue occasions compared to control at[Week X]

Rescue Medication Endpoints:
The use of rescue medication, sometimes referred to as reliever medication, is a sign of inadequately controlled asthma and has been included as a parameter in several asthma control instruments.
The protocol should specify that rescue beta-agonist use be captured separately from prophylactic (eg, prior to exercise) use and reporting. The frequency of rescue occasions, not puffs, should be documented. This also standardizes various rescue agents (eg, some may take one puff, others two puffs).
Exploratory

To evaluate the allergic response to [x mg of Study Treatment to the skin prick test]

/ Allergen Skin Test
The response to the standard skin prick test at [Week X]
Allergen Skin Test Endpoints:
Skin testing is conducted to document the allergens to which a participant shows an specific IgE mediated allergic reaction. A standard skin prick test can be utilized for this purpose. The endpoint associated with this variable can be ‘positive’ or ‘negative’ based on a threshold wheal size clearly described in the protocol. Cross reference to the Section 10 to describe the planned analysis for the binary results.

5.Study Design

Spirometry Tests in Asthma- Spirometry measures may be misleading if there is variability in effort. The FEV1 and FVC are common measures of efficacy in asthma studies. The FEV1 is the most reproducible of all spirometry measuresbecause most individuals can generate maximal effort for 1 second. Thus, it is highly regarded as a reliable and consistent primary efficacy endpoint. The PEF has greater variability and is not recommended as a primary endpoint.

Definitions of Common Assessments

Forced Expiratory Volume in 1 second (FEV1) is the volume (L or mL) of air that is exhaled in the first second of a forced spirometry test.
Percent Predicted FEV1 is the participant’s best FEV1 for the assessment divided by the participant’s predicted normal value multiplied by 100.
Forced Vital Capacity (FVC)is the volume of air expired over the course of a forced, maximal exhalation after a full inhalation. It is equal to the sum of inspiratory reserve volume, tidal volume, and expiratory reserve volume.
Percent Predicted FVC is the FVC value divided by the participant’s predicted normal value, multiplied by 100.
Peak Expiratory Flow (PEF) is the maximal flow rate (L/sec or L/min) achieved during a maximally forced exhalation. The PEF is quite variable and not recommended as a primary endpoint.
Percent Predicted PEF is the maximal flow rate achieved during a maximally forced exhalation divided by the participant’s predicted normal value.
FEV1/FVC Ratio (or percentage) provides a measure of the proportion of total FVC that is expelled during the first second of a forced exhalation. This measure is a good index of airflow obstruction.
FEF25-75is forced expiratory flow at 25% to 75% of vital capacity, also called maximal mid-expiratory flow (L/sec).
Percent predicted FEF25-75is the FEF25-75 value divided by the participant’s predicted normal value, multiplied by 100.

Notes:

Healthcare utilization (frequency of ER visits, number of hospitalizations related to asthma symptom managementoccurring during a specified period)is out of scope for this versionof this library.

Biomarkers are out of scope for this version of this library.

10.3 Statistical Analyses

Points to consider for this section

Overall rate (number of events requiring systemic corticosteroids/time interval specified in the study)
Weighted mean rate (total exacerbations in the treatment group/total participant-time in the group)
Time to first exacerbation
Percentage of treatment group with an exacerbation

11.0 References

Reddel HK, Taylor DR, Bateman ED, et al.An official American Thoracic Society / European Respiratory Society statement:asthma control and exacerbations:standardizing endpoints for clinical asthma trials and clinical practice.Am J RespirCrit Care Med. 2009; 180(1);59-99.
Chung KF et al. ERS/ETS Guidelines on severe asthma EurRespir J 2014; 43:343-373.
Quanjer PH, Tammeling GJ, Cotes JE et al.Lung volumes and forced ventilator flows.Report Working Party Standardization of Lung Function Tests, European Community for Coal and Steel.Official Statement of the European Respiratory Society.EurRespir J 1993; 6:Suppl. 16:5-40.
Tojo N, Suga H, Kambe M.Lung Function Testing – The Official Guideline of the Japanese Respiratory Society.RinshoByori 2005 53(1):77-81.
Clinical Data Interchange Standards Consortium (CDISC), Version 1 of Therapeutic Area Data Standards User Guide for Asthma, November 26, 2013.

Pulmonary Function Test Manual (not included with this template)

The Pulmonary Function Testing (PFT) Manual should be created as a separate document ifcertain endpoints are selected. The PFT Manual clearly outlines detailedmethods for PFT measurements. It is viewed as an extension of the protocol; thus, careful alignment with the protocol is a necessity. The CDISC Therapeutic Area Data Standards (Version 1 released 26 Nov 2013) spirometry procedures1 (Page 24) should be used as a reference to provide standardization across protocols.

Spirometry Testing Procedure:

Spirometry is the most important type of PFT for asthma clinical trials because it measures the flow rates and volumes of both exhaled and inhaled air. A spirometry test session is one in which the participant performs several effective exhalations (seebelow for acceptability of measurements). Spirometry measures should be assessed at approximately the same time of day (+/- 2 hours) due to diurnal variation in lung function.

Central/Core Laboratory: Central readers are PFT experts who review the results of a spirometry test for accuracy and consistency. For a clinical trial with a central over-read vendor/laboratory, consult with the regulatory authority on whether the two ‘best’ results identified in the statistical section of the protocol are those of the assessor at the investigative site or those of the central reader. The statistical section of the protocol should identify that a ‘best of two assessments' will be used for each variable. The statistical section should also clarify the source of the ‘best’ of two values that are measured for each variable (eg, -central reader-selected ‘best’ FEV1 or local reader-selected ’best’ FEV1).

Methodology: The manual must identify the method (device type) used to perform the test and assessment. Instructions for test administrationin order to obtain themost consistent results should be detailed. The algorithm used in the calculation of the predicted value for each participantshould be described.

Baseline Spirometry Assessment: Define the “baseline” assessment for each variable. This is an important aspect to consider for endpoints that measure change from baseline. This can be designated as the screening visit or the pre-treatment assessment on the first day of study treatment. The Schedule of Activities (SoA) should identify the baseline assessment and Section 10 Statistical Considerations should cross reference the SoA.

Acceptability of Measurement: At each spirometry assessment timepoint, the test administrator (eg, technician) will check each replicate (effort)from the participant for acceptability. An acceptable effort is one with good start and satisfactory duration of exhalation and without coughing or other technical interruptions or problems. The two largest FEV1 values must be within 150 mLof each other. Similarly, the two largest FVC values must be within 150 mLof each other. The highest value from an acceptable effort is taken as a best result. The highest value foreach parameter (eg, FEV1 andFVC) may come from different efforts.

Timing of Assessments Relative to Rescue Inhaler: Pre-bronchodilator (trough) FEV1 is defined as a FEV1 recorded after withholding short-acting beta agonists (SABA) and long-acting beta agonists (LABA) for a period appropriate to their duration of action (eg, ≥X hours for SABA and ≥12 hours for LABA). The procedures section of the protocol should provide detail on the number of repeat measures of assessments and corresponding timepoints before and after treatment (Reference: 3.1.2 of CDISC identifies steps for spirometry procedures).

Medical History of Asthma: Date of diagnosis of asthma should be clearly described in the screening visit medical history. This can be open to interpretation andr equires a clear definition of this date in the protocol. The severity of asthma should be collected.1

Interpretation of Results: All results obtained from PFTs must be compared with reference values to determine the presence and degree of abnormality. Published reference values utilizing national datasets are available. The most recent widely used dataset is from the third National Health and Nutrition Examination Survey (NHANES III) which assessed non-smoking participants (8 to 80 years old) of Caucasian, African-American, and Mexican-American ancestry. The NHANES III database is also applicable to Caucasian groups of European ancestry. For the “percent predicted” spirometry measures, the participant’s result is reported as a percent of the predicted value generated from NHANES data and reflecting equations that incorporate age, gender, height, and race for a representative healthy population.1,2 The most recent statements from the ATS and ERS recommended use of NHANES III reference equations for people8 through 80 years old in the United States. Although a joint statement, no recommendation for EU laboratories wasmade. Consult with the regulatory authority reviewer for advice. If alignment withNHANES III is not acceptable to the regulatory authority, the alternative is the use of values from the European Community for Coal and Steel.3 Guidelines for the Japanese Respiratory Society should be followed for studies in Japan.4